The α-arylation of active methylene carbonyl compounds has become a widely used method, which provides an easy access to important classes of biologically active natural/synthetic products. This transformation is usually carried out by transition-metal-catalyzed reactions in combination with a variety of ligands and additives or rarely by using organocataylsis. Introduction of the “Benzyne” species to the scientific community in 1953 by Professor John D. Roberts, the founder of benzyne chemistry, opened up a new avenue for the chemists to explore. Particularly, fluoride-induced milder reaction condition for in situ generation of arynes has captured the attention of synthetic organic chemists. Since then the high reactivity of arynes due to its distinct electrophilicity has been utilized efficiently and has resulted into a diverse range of useful compounds including complex bioactive natural products.
The most commonly observed and well-studied reactions are the insertion of arynes into the element-element σ-bond and -bond, however examples of aryne insertion into the C—H σ-bond to directly provide C-arylated products are rare and till date known on few substrates like anilines, aldehydes and β-enamino esters/ketones. Literature survey revealed that in the case of α-unsubstituted β-dicarbonyl compounds have observed insertion of benzyne into C—C σ-bond as the only product. It has also noticed the C-arylation as product on only one of the substrate α-methyl β-keto ester.
Moreover, the insertion of benzene rings into the amide bond using the reactive intermediate benzyne wherein, the aromatic amides undergo smooth insertion when treated with O-triflatophenyl silane benzyne precursors, producing versatile amino benzophenone products in good yield is reported in Org. Lett., 2010, 12 (1), pp 168-171 by Didier G. Pintori et al. and Yeeman K. Ramtohul et al. in Org. Lett., 2007, 9 (6), pp 1029-1032.
A protocol for the efficient synthesis of substituted and polycyclic o-diiodoarenes, wherein diiodination process involves the formal insertion of arynes into the I—I σ-bond is demonstrated by Diego Rodriguez-Lojo et al in Org. Lett., 2012, 14 (6), pp 1363-1365.
Further a facile synthesis of n-alkyl-n′-arylimidazolium salts via addition of imidazoles to arynes in presence of palladium-catalyst is disclosed in Org. Lett., 2002, 4 (16), pp 2767-2769 by Hiroto Yoshida.
References may be made to Journal, J. Am. Chem. Soc., 2005, 127 (38), pp 13112-13113, wherein Zhijian Liu et al. discloses an efficient, mild, transition-metal-free method for the intermolecular C—N σ-bond addition of amides and S—N σ-bond addition of sulfinamides to arynes to form one C—C bond and one heteroatom-carbon bond in one step at room temperature.
Metal-catalyzed alpha-arylation of monocarbonyl and related molecules with C—C bond formation by C—H bond functionalization and palladium-catalyzed alpha-arylation of ketones is disclosed in Angew Chem Int. Ed Engl. 2010; 49(4):676-707 and Acc Chem Res. 2003 April; 36(4):234-45 respectively, whereas metal free sulfoxide-mediated α-arylation of carbonyl compounds is reported in J. Am. Chem. Soc., 2011, 133 (22), pp 8510-8513 by Xueliang Huang et al.
An efficient route to a variety of 2-phenylindolin-3-ones from amino acid methyl esters is known from Chem. Commun., 2011 (47), 5822-5824.
It is observed that mono/diarylation of α-unsubstituted β-dicarbonyl compounds and arylation of α-substituted β-dicarbonyl compounds to construct stereocenter at milder reaction conditions has not been reported in the literature.
Therefore, α-arylation as a process to arrive at compounds with a chiral center is not known. Also, there are no simple processes available in the art that use α-arylation operated at room temperature as the preferred route to synthesize compounds with a chiral center. Generally high temperatures and use of expensive palladium catalysts, acid sensitive and corrosive solvents like TBAT and TFAA, very strong bases like sodium tert. butoxide and longer reaction times are required to carry out such transformations. Longer reaction times and higher temperature results into lower optical purity (low enantiomeric excess) of the final compounds. Further the processes known in the art need an activated aryl compound if the reaction is to be done at milder conditions.
Further the transition-metal-free direct α-aryiation of β-dicarbonyl compounds at room temperature using aryne intermediates has not been reported in the literature.
In order to overcome the drawbacks in the art, the inventors propose a room temperature one-pot process for α-arylation using benzyne intermediate. Therefore the present inventors have succeeded to overcome the difficulty by using β-dicarbonyl ester-amides as the starting material, wherein the obtained arylated compounds may be useful for synthesis of CNS depressant barbiturate drugs like Phenobarbital.